KR101286029B1 - Resorbable polyether esters and use thereof for producing medical implants - Google Patents

Abstract

The present invention relates to the use of absorbent block copolymers comprising polyethers and polyester units and to corresponding block copolymers for producing surgical implants suitable for human or animal organisms. The novel block copolymers are characterized by high mechanical strength and fast absorption kinetics.

Absorbent Polyether Ester, Medical Implant, Absorption Kinetics

Description

Resorbable polyether esters and use thereof for producing medical implants

The present invention relates to absorbent block copolymers having a polyether and polyester units (hereinafter referred to as 'poly (etherester)') and their use for producing surgical or therapeutic implants for the human or animal body. The block copolymers and implants made therefrom according to the invention are characterized by improved absorption kinetics while at the same time having high mechanical strength. Throughout the specification, the preparation and purification of block copolymers according to the invention have been described.

Absorbent polymers are becoming increasingly important as additives in pharmaceutical formulations or biodegradable implants. Polymers with obviously different physical and chemical properties are needed in all kinds of technical fields.

Thus, as additives for pharmaceutical formulations, block copolymers having polyester and polyether units are used in particular as carrier materials for the active substances or as materials for microencapsulation of the active substances. In this case, the polymer is preferably provided by parenteral routes. In the case of a carrier material, this method of use assumes that the material can be mixed with other ingredients of the formulation in powder, in solution or in suspension without loss of quality. In the case of microencapsulation, it is also true that the polymer used behaves in a chemically and physically neutral manner with respect to the other components of the formulation. A further requirement is that the microcapsules must release the active substance at the target site. Natural brittle or hard materials are excluded from this field. In the art, poly (etheresters) of type AB, ABA, BAB or ABABABAB have been found to be particularly suitable. Examples include polymers having L-lactide as A-blocks or polyethyleneglycol as D, L-lactide and B-blocks.

In addition to being used in the pharmaceutical field, interest in absorbent polymers for professionals in surgery and surgical treatment continues to increase. When selecting a material that appears to be suitable in the art, it is important to consider the mechanical properties of the material, and its toxic properties, unlike in the pharmaceutical field. Solid materials are used that satisfy the toxic and mechanical profiles while also satisfying the properties necessary for manufacturing and processing. Thus, the material must be able to be processed by thermoplastic processing methods such as injection molding, melt compression or extrusion or must be able to withstand the needs of mechanical methods such as machining. Essential properties in this regard are mainly strength and decay rates under tensile or torsional stresses.

The nature of the implant is measured mainly by the materials used and, less often, by their processing.

Absorbent implants have advantages over nonabsorbable materials, for example metals, after they meet their function in the human or animal body, they are hydrolytically degraded and the degradation products are reabsorbed by the body. Thus, there is no need to remove the implant in the second process. A further advantage of absorbent implants is that there is a risk of bone atrophy of the bone due to inactivation, for example in bone synthesis (in the case of non-absorbable implants, once the implant is removed, it can increase the risk of new fractures in the bone). As demonstrated by the example, the material has excellent resistance to the material. Polymers that are important for surgical purposes and are absorbent should also have other properties such as high strength.

Known absorbent polymers suitable for surgical implants are, for example, lactide (= 3,6-dimethyl-1,4-dioxane-2,5-dione), glycolide (= 1,4-dioxane- 2,5-dione), dioxanone (1,4-dioxan-2-one), lactide / glycolide and trimethylene carbonate (= 1,3-dioxan-2-one) and ε-caprolactone Aliphatic poly (ester) based on copolymers thereof. Preferably, a high molecular weight is used. Examples include poly (L-lactide), poly (D, L-lactide), poly (L-lactide-co-D, L-lactide), poly (D, L-lactide-co-glycolide ), Poly (glycolide), poly (L-lactide-co-glycolide), poly (glycolide-co-trimethylene carbonate), poly (L-lactide-co-trimethylene carbonate), poly (D , L-lactide-co-trimethylene carbonate), poly (L-lactide-co-caprolactone).

Using the materials described above, it is possible to produce absorbent implants that occupy a broad spectrum with respect to their mechanical properties. For example, poly (L-lactide) has not only high strength but also excellent stiffness and brittleness, where copolymerization of D, L-lactide with trimethylene carbonate produces a material having viscous properties Let's do it. In view of its degradation rates of months to years, the material is particularly suitable for implants which remain in the body for a considerable length of time.

On the other hand, faster degradable materials and implants often have unmet needs in surgery. In particular, in the case of pediatric applications and implants for fastening fast-proliferating tissues, there is a need for materials that decompose relatively quickly but still have mechanical properties such as the required strength, elasticity, tenacity and the like.

The present invention contributes to the provision of such materials. Indeed, surprisingly, polymer block copolymers of type AB or ABA suitable for the production of implants with improved properties by ring-opening polymerization of cyclic esters in the presence of monofunctional or difunctional poly (ethyleneglycol) under appropriate synthetic conditions It has been found that can be produced simply on an industrially available scale. These polymers may also be purified on an industrial scale by simple methods such as extraction processes so that their purity meets the requirements for body transplantation. In addition, they have the property of being able to process materials by simple thermoplastic molding methods to produce implants.

Object of the present invention

It is an object of the present invention to provide a material for making medical and surgical implants that are degraded more quickly by the human or animal body than materials known from the prior art, but at the same time have a high mechanical strength, for example tensile strength. .

A further aim is to provide a material for making medical and surgical implants having physical properties suitable for the implant. These include, for example, initial strength, elasticity or non-tension.

It is a further object of the present invention to provide a material according to the invention with a degree of purity that is intended for use in the human or animal body. It is particularly important to obtain a low content of synthetic starting materials in the final material.

A further aim of the present invention is to provide a material for a surgical implant that is absorbed quickly enough for use in the pediatric field or as an implant for fixing fast-proliferating tissue.

It is a further object of the present invention to provide a method that can be used on an industrial scale to produce raw materials for the implants described above.

It is a further object of the present invention to provide a medical implant and a method of making the same.

The present invention relates to a block copolymer consisting of polyester units and polyether units for producing absorbent surgical implants.

In a preferred aspect, the invention relates to an implant comprising the block copolymer according to the invention.

The term implant refers to a shaped body which is both surgically and mechanically suitable for introduction into the human or animal body and which is not toxically opposing (absorbent). Such shaped bodies may be screws, pins, plates, threaded nuts, anchors, down, films, membranes, meshes and the like. They can be used to fix hard tissue fractures, as suture anchors, as spinal implants, to close and fix blood vessels and other vessels, as stents, or to fill a cavity or hole in tissue defects.

The block copolymers according to the invention are also suitable, for example, for the preparation of drug eluting stents. These are vascular supports for placement into arterial vessels, which release proliferative-inhibiting active substances to surrounding tissue to prevent restenosis over time. Active substances selected from cell growth inhibitors such as paclitaxel have been found to be successful for this purpose, for example.

The implants according to the invention can be produced from materials by thermoplastic molding methods, for example, to produce the shapes required for medical use, for example screws. Suitable molding processes are processes known per se from the prior art for thermoplastics, for example melt compression, preferably extrusion and injection molding processes. Particular preference is given to molding by an injection molding process.

Suitable temperatures for injection molding depend on the exact copolymer composition and are between 110 and 210 ° C. Because higher processing temperatures are required for higher molecular weight block copolymers, the melt viscosity is higher than for relatively low molecular weight polymers. Due to its crystallinity, high processing temperatures are also required for block copolymers having a high proportion of L-lactide units.

Since they are susceptible to hydrolysis, it is also advantageous to dry the block copolymer and maintain the processing temperature as low as possible before processing.

The block copolymers according to the invention used are type AB or type ABA polyetheresters.

A is a polymer block having repeating ester units and B is a polymer block having repeating ether units.

The polyester block A consists of n components which can be formally derived from one or more hydroxycarboxylic acids or carbonates, preferably α-hydroxycarboxylic acids. If desired, block A may be formally synthesized from several different of these components.

B represents a polyether unit whose repeating unit is formally derived from ethylene glycol. The repeating unit may be present in m times.

The polymer according to the invention is prepared by synthesizing polyester block (s) A on polyethylene glycol block B with one or two free terminal OH groups. Thus, polyethylene glycol blocks having two free terminal OH groups are used for ABA type polymers, while polyethylene glycol blocks having only one free terminal OH group are used for AB type polymers.

The AB type polyetherester according to the present invention may be a compound of formula (I).

E- (OD-CO-) _n- (O-CH ₂ -CH _2- ) _m -OF

In the above formula (I)

Structural unit E-(-OD-CO-) _n -forms block A,

Block A is connected to block B through a covalent bond,

D is, independently of each other, for each n unit:-(CH (CH ₃ )-) _x ,-(CH _2- ) _x ,-(CH ₂ -O-CH ₂ -CH _2- ) or-(CH ₂ -CH ₂ -CH ₂ -O-),

x is 1, 2, 3, 4 or 5,

E is H, methyl or ethyl,

n is an integer greater than 1,

The structural unit-(O-CH ₂ -CH _2- ) _m -OF forms a block B,

F is H, methyl or ethyl,

m is an integer greater than one.

It should be clearly pointed out that the AB block copolymer is structurally identical to the BA block copolymer and for this reason there is no difference within the scope of the present invention.

ABA block copolymers are polymers of formula (II) based on the above definitions.

E (-OD-CO) _n- (O-CH ₂ -CH _2- ) _m -O- (CO-DO-) _{n '} -E

In the above formula (II)

All variables in the definitions are provided above,

n 'is an integer greater than one.

As is common in polymers, n, n 'and m are numbers representing the statistical average chain length of two blocks. The exact number in each individual molecule is treated as a statistical distribution.

The length of the B blocks in the copolymer may be on average 500 to 10,000 daltons. While an average block length of 600 to 8,000 Daltons is preferred, an average block length of 1,000 to 8,000 Daltons is particularly preferred. Short-chain poly (ethyleneglycol) fragments released by the hydrolytic decomposition of the block copolymers are easily released by the body through the kidneys.

At this point, it should be mentioned that all ranges described in this specification are included in each case.

The weight ratio of A block to B block plays an important role in relation to the properties of the copolymer and the implants made therefrom according to the invention. The higher the amount of B blocks, the more hydrophilic materials, which have a positive effect in terms of fast absorbency (hydrolysis or rate of degradation).

According to the invention, the weight ratio of the B blocks is from 0.01 to 25%. The following sequence provides the preferred proportions of B in the ascending order of priority for each embodiment: 0.01-20 wt%, 0.1-15 wt%, 0.1-10 wt%, 0.1-5 wt%, 0.1-4 wt% , 1 to 3% by weight. Particular preference is given to polymers having the last third amount of B. In fact, it was surprisingly found that with only a small amount of hydrophilic B blocks in this embodiment, hydrolytic degradation can be significantly accelerated compared to the corresponding pure poly (ester) A.

Most preferred are polymers comprising a proportion of B in the range from 0.1 to 4% by weight. This is particularly advantageous as a molded article comprising a block copolymer with a higher predominance in the A block. Accordingly, embodiments comprising an amount of B in the range of 1 to 3% by weight, in particular 0.5 to 1.5% by weight, are more preferred in this respect.

The above detailed description of the length of block B and its weight ratio in the polymer automatically provides the block length of the A block (s) and thus the total molecular weight as a whole. In the case of the ABA type triblock copolymer, it is assumed that the length and weight ratios of the two blocks A are equal on average. Similarly, the total molecular weight of the copolymer is determined by the molecular weight of the ethylene glycol used in the synthesis and the ratio of the two components introduced.

It should be pointed out that naturally the molecular weight of the final block copolymer may be limitedly determined by the length and proportion of block B.

Intrinsic viscosity (i.v.) can be used as another important parameter that characterizes the polymers suitable for the use according to the invention. The inherent viscosity of the block copolymer can vary widely. Preference is given to an intrinsic viscosity of 0.1 to 6 dl / g, preferably 0.5 to 5 dl / g (measured with a Ubbelohde viscometer in chloroform at 25 ° C. in a 0.1% solution). Particular preference is given to values of 0.6 to 3 dl / g, most particularly preferred to values of 0.7 to 2.75 dl / g.

AB or ABA type block copolymers having the following characteristics are preferred according to the invention.

Intrinsic viscosity (measured in chloroform at 25 ° C. in a 0.1% solution) is 0.1 to 5.5 dl / g, preferably 0.5 to 5.0 dl / g.

The average block length in the B blocks is from 1,000 to 8,000 daltons.

The weight ratio of B blocks is from 0.1 to 15% by weight, preferably from 0.1 to 5% by weight, more preferably from 0.1 to 4% by weight.

Block A preferably has the following ester component.

 Exclusively L-lactide, D-lactide, meso-lactide or DL-lactide,

 Exclusively L-lactide,

 Exclusively D, L-lactide,

 A mixture of statistically distributed (randomized) L-lactide with D, L-lactide, preferably having a molar ratio of L-lactide of 60 to 90%,

 Preferably statistically distributed (random) with a molar ratio of L-lactide of 70 to 99%, more preferably 85 to 99%, more preferably 70 to 95%, more preferably 87 to 95% Mixture of L-lactide and glycolide).

 A mixture of statistically distributed (randomized) D, L-lactide with glycolide, preferably having a molar ratio of D, L-lactide from 50 to 80%.

 Statistically distributed (randomized) L-lactide, D-lactide, meso-lactide or mixtures of DL-lactide units with ε-caprolactone units.

 Statistically distributed (randomized) L-lactide or a mixture of D, L-lactide units with ε-caprolactone units.

 Statistically distributed (randomized) L-lactide, D-lactide, meso-lactide or mixtures of DL-lactide units with dioxanone units.

 Statistically distributed (randomized) L-lactide or a mixture of D, L-lactide units with dioxanone units.

 Statistically distributed (randomized) L-lactide, D-lactide, meso-lactide or mixtures of DL-lactide units with trimethylene carbonate units.

 Statistically distributed (randomized) L-lactide or a mixture of D, L-lactide units with trimethylene carbonate units.

Block A is more preferably a block copolymer comprising the following ester component.

 Exclusively L-lactide,

 Exclusively D, L-lactide,

 A mixture of statistically distributed (randomized) L-lactide with D, L-lactide, preferably having a molar ratio of L-lactide of 60 to 90%,

 A mixture of statistically distributed (randomized) L-lactide with glycolide, preferably having a molar ratio of L-lactide of from 70 to 95%,

 A mixture of statistically distributed (randomized) D, L-lactide with glycolide, preferably having a molar ratio of D, L-lactide from 50 to 80%.

 The implant according to the invention preferably comprises one or more different ones of the block copolymers according to the invention and does not contain any additives other than impurities from the polymerization process. In one particular embodiment, the implant may be a polymer block copolymer and other absorbent materials such as poly (L-lactide), poly (D-lactide), poly (D, L-lactide), poly (meso) Absorbent polys selected from-lactide), poly (glycolide), poly (trimethylene carbonate), poly (dioxanone), poly (ε-caprolactone), and copolymers of the corresponding heterocyclic groups or polyethyleneglycols It may also contain a blend with (ester). Preference is given to blends in which the chemical structure of the A block in the block copolymer corresponds to the chemical structure of the poly (ester). This ensures good phase coupling in the blend, which is advantageous in achieving good mechanical properties. Blends of different block copolymers may be used.

The weight of the implant according to the invention may be 1 to 10,000 mg, preferably 5 to 5,000 mg, particularly preferably 10 to 1,000 mg.

The preferred tensile strength of the implant, measured according to ASTM standard D 638, prepared according to the invention from the polymers described above, is at least 70 MPa, preferably 75 to 95 MPa, particularly preferably 80 to 88 MPa.

The preferred rate of hydrolysis (decomposition rate) of the implant (which is prepared according to the invention from the polymer described above) measured as a change in intrinsic viscosity in the molded article according to ASTM standard D 638 is aqueous at 37 ° C. after 6 weeks at pH 7.4. In a bath consisting of phosphate buffer, at least 30%, preferably at least 40%, particularly preferably at least 45%, based on the starting value.

The invention further relates to an implant characterized in that it comprises a blend consisting of component (a) and component (b).

(a) a block copolymer according to the invention and

(b) an absorbent poly with lactide repeating unit selected from L-lactide, D-lactide, D L-lactide or meso-lactide, glycolide, trimethylene carbonate, ε-caprolactone or dioxanone Ester A, where only similar or different among the units described may be present.

Preparation of block copolymers

AB type copolymers can be synthesized by ring-opening polymerization of cyclic esters with free hydroxyl groups and non-reactive end groups, where methoxy end groups are preferred, in the presence of poly (ethylene glycol). ABA type copolymers can be prepared with two free hydroxyl groups in the presence of poly (ethyleneglycol). In this case, two blocks A are synthesized simultaneously in the same synthesis step.

Cyclic esters of formula III serve as components for the ring-opening polymerization to prepare block (s) A.

In formula (III) above,

D in each unit of —O—D—CO has one of the definitions described above independently of one another.

z is an integer of 1 or more, Preferably it is 1 or 2. Especially preferably, dimeric cyclic esters, monomeric lactones or cyclic carbonates of α-hydroxycarboxylic acids are used.

When preparing block (s) A, it is not necessary to use only one type of component according to formula III. Mixtures with different chemical properties of the structural element D may also be used.

Preferred structures according to formula III, or preferred molecules in which block A is formed by ring-opening polymerization, are a) L-lactide, b) D-lactide, c) a mixture of D-lactide and L-lactide, For example racemic D, L-lactide, d) meso-lactide, e) glycolide, f) trimethylene carbonate, g) ε-caprolactone, h) dioxanone, i) L-lac A mixture of tide with D, L-lactide, j) a mixture of L-lactide with glycolide, k) a mixture of D, L-lactide with glycolide, 1) a L-lactide or D, L A mixture of lactide and trimethylene carbonate, m) L-lactide or a mixture of D, L-lactide and ε-caprolactone.

a) L-lactide, b) L-lactide and glycolide, c) L-lactide and D, L-lactide, d) D, L-lactide in the proportions described above (see Description of Polymers) And glycolide are particularly preferred.

In order to produce poly (etherester), it is advised to use raw materials in high purity. In particular, polar-protic impurities such as water cause chain breakdown during the polymerization reaction. For this reason, it is advised to dry poly (ethyleneglycol) before use in polymerization.

For the synthesis, poly (ethyleneglycol) is mixed and melted with one or more monomers or dimers according to formula III. After the adducts are homogeneously mixed, the catalyst to be used in the ring opening polymerization is added. The reaction mixture is preferably polymerized at elevated temperatures.

Many different metal catalysts such as tin or zinc compounds are suitable for the synthesis. Tin (II) chloride or tin (II) ethylhexanoate is preferably used. In view of the proposed use in the human or animal body, it is advantageous to use the smallest amount of catalyst possible. A concentration of 30 to 200 ppm is preferred and a concentration of 50 to 100 ppm is particularly preferred. In each case the concentrations described for the catalysts are called catalytic metal ion parts by weight based on the total reaction mass.

The reaction temperature is above the melting point of the adduct used in each case and therefore depends on the structure of the monomer (s) or dimer (s) according to formula III and the molecular weight of the poly (ethyleneglycol) used. In general, the operation is carried out in the temperature range of 100 to 160 ℃. While a range of 100 to 140 ° C. is preferred, a range of 110 to 130 ° C. is particularly preferred. In polymers where good solubility in organic solvents is important, the reaction temperature can be adjusted from 150 ° C to 170 ° C. High reaction temperatures favor good statistical distribution of comonomer units in the A block (s). In this way, for example, glycolide-containing polymers which are readily dissolved in acetone can be prepared.

The required reaction time depends on the reaction rate, the reaction temperature and also the catalyst concentration of the monomer (s) or dimer (s) of formula III used, and ranges from several hours to several days. Reaction times of 24 hours to 5 days are preferred, while times of 2 to 5 days are particularly preferred. The longer the reaction time, in general, the higher the conversion, which in turn contributes to the reduction in duct concentration in the final product.

In summary, the relevant reaction parameters, ie catalyst amount, reaction temperature and reaction time, in terms of the minimum possible catalyst content, avoid the adducts used, the decomposition and decolorization reactions in the product and the most expensive possible reactions of monomers or dimers. It is selected according to the reaction temperature suitable for doing so.

In general, polymers prepared according to the above description are also subjected to a purification process. The ring-opening polymerization of the adducts according to formula (III) is an equilibrium reaction, and the remaining amount of unreacted adduct is still present in the coarse polymer, which may be disadvantageous for subsequent processing and implantation.

Purification of the polymer can be carried out by precipitation or extraction from various solvents.

For precipitation, the coarse polymer is dissolved in a solvent miscible with a precipitant, for example acetone, methylethylketone, glacial acetic acid, a mixture of glacial acetic acid and acetone, DMSO, methylene chloride, chloroform or a mixture of methylene chloride and chloroform, The resulting solution is mixed with water, methanol, ethanol or other alcohols as precipitant. Other solvents / precipitants, such as precipitation in ethers, are conceivable, but are not preferred on an industrial scale for toxicity or safety considerations. Amorphous polymers that are difficult or impossible to purify by extraction are often purified by precipitation.

Extraction process is preferred. The crude polymer obtained is extracted with a solvent and then dried. For extraction, the crude polymer is generally pre-milled to ensure proper diffusion of the solvent into the solid. For the purification process, organic solvents and supercritical or pressure-liquefied gases are suitable, which dissolve the monomer but do not dissolve the polymer. Preferably an organic solvent selected from n-alkane or cyclo-alkane (cyclo-hexane or n-hexane at ambient temperature) and carbon dioxide is used, particularly preferably supercritical or pressure-liquefied carbon dioxide.

The invention thus further

Mixing and melting poly (ethyleneglycol) with one or two free terminal OH groups together with one or more monomers or dimers of formula III, (a),

Adding the metal catalyst to the homogeneous mixture obtained in step (a) (b),

(C) polymerizing the mixture of step (b) at a reaction temperature above the melting point of the adduct used for a reaction time of 24 hours to 5 days,

(D) purifying the crude polymer obtained in step (c) by precipitation or extraction from a solvent and

It relates to a process for the preparation of AB and ABA type poly (etheresters) according to the invention, comprising the step (e) of grinding the polymer obtained in step (d).

(III)

In formula (III) above,

D in each unit of -OD-CO is independently of each other-(CH (CH ₃ )-) _x ,-(CH _2- ) _x ,-(CH ₂ -O-CH ₂ -CH _2- ) or-(CH ₂ -CH ₂ -CH ₂ -O-),

x is 1, 2, 3, 4 or 5,

z is an integer of 1 or more, preferably 1 or 2.

Preferably, the poly (ethylene glycol) used in step (a) is dried in advance. More preferred embodiments can be deduced from the foregoing.

Preparation of Implants

The obtained polymer block copolymers can be easily processed into surgical implants, which still have high initial strength, while having the desired rapid degradation properties compared to implants known from the prior art by thermoplastic formation.

Implants According to the Invention of  Usage

Implants according to the present invention can be used, for example, to fix hard tissue fractures (osteosynthesis), to control tissue resynthesis in soft tissues, to fix sutures in bones (seal material anchors), to intervertebral ligaments (eg : Spine implants to protect so-called "vertebral cages"), in tissue defects as stents, for example in dentistry or in heart diaphragm defects, in order to close and fix blood vessels and other vessels in vascular rupture (anastomosis) It can be used to fill a cavity or hole and to fix tendons and ligaments in the bone. To this end, the block copolymer is processed into shaped articles, the design of which is used in certain applications. Thus, for example, screws, pins, plates, nuts, anchors, down, films, films, meshes and the like can be obtained. Screws of this kind can be produced, for example, in various sizes, in different tread sizes, in right- or left-handed treads, in different screw heads such as cross-heads, or in single slots. Other possible uses can be inferred from the prior art.

The following examples are provided to illustrate examples without limiting the invention to the content thereof and are intended to be understood only as possibilities.

One. In the lab  Decay experiment

The polymers according to the invention are processed using injection molding processes known from the prior art to form shaped articles (test pieces). They are fixed in a wire mesh and placed in a hydrolysis bath controlled to a temperature of 37 ° C. It is filled with phosphate buffer solution at pH 7.4, which changes weekly. Samples are taken at a fixed test time. Degradation of the polymer is observed by changing the parameters of intrinsic viscosity (i.v.) over time (measured by Uberode viscometer in chloroform at 25 ° C. in a 0.1% solution).

1.1 Poly  L- Lactide - Polyethylene glycol  Diblock or triblock copolymer

The following materials are used.

ABA type polymers having L-lactide as components of the A block and 1% and 5% polyethyleneglycol 6000 (PEG 6000) as the B block and

AB type polymer with L-lactide as component of A block and 1% and 5% polyethyleneglycol 2000 (PEG 2000) as B block. The numbers 2000 and 6000 represent the molar weight of PEG in Daltons.

The value measured for intrinsic viscosity at time O is normalized to 100%. This corresponds to the value before the specimen was submerged in the hydrolysis bath. To measure degradation, the measured values are reported in percentages based on the starting value.

The following materials are used as AB polymers.

Sample 1: L-lactide-polyethyleneglycol with 1% polyethylene glycol (PEG) by weight and molar weight 2,000 Daltons. Thus, the length of the A block is calculated as 198,000 Daltons.

Sample 2: L-lactide-polyethyleneglycol having 5% by weight polyethylene glycol (PEG) and molar weight 2,000 Daltons. Therefore, the length of the A block is calculated as 38,000 Daltons.

The following materials are used as ABA polymers.

Sample 3: L-lactide-polyethyleneglycol-L-lactide having 1% by weight polyethylene glycol (PEG) and molar weight of 6,000 Daltons. Thus, the length of the A block is calculated as 297,000 daltons in each case.

Sample 4: L-lactide-polyethyleneglycol-L-lactide having a weight ratio of 5% polyethyleneglycol (PEG) and a molar weight of 6,000 Daltons. Thus, the length of the A block is calculated as 57,000 daltons in each case.

result:

Table 1 below provides an overview of the degradation rates of the polymers used.

i.v .: Intrinsic viscosity (measured by Uberode viscometer in chloroform at 25 ° C in 0.1% solution)

n.d .: Not measured

In the AB diblock copolymer, the following values are obtained after 18 weeks.

Sample 1: 52% of starting value

Sample 2: 38% of starting value

In ABA triblock copolymers (Samples 3 and 4), hydrolytic degradation after 8 weeks produces an intrinsic viscosity that constitutes only about 25% of the starting value, regardless of whether 1 or 5% PEG is selected.

As a comparison: the values for poly L-lactide are in the region of only 60% after 20 weeks.

1.2 Poly  L- Lactide -Nose-D, L- Lactide - Polyethylene glycol Eblock  or Three blocks  Copolymer

The following materials are used.

ABA type polymer having L-lactide-co-D, L-lactide and 5% polyethyleneglycol 2000 (PEG 2000) as the B block and

AB type polymer with L-lactide-co-D, L-lactide and 5% polyethyleneglycol-MME 5000 (PEG-MME 5000) as a component of the A block. The numbers 2000 and 5000 represent the molar weight of PEG or PEG-MME in Daltons.

The value measured for intrinsic viscosity at time O is normalized to 100%. This corresponds to the value before the specimen was submerged in the hydrolysis bath. To measure degradation, the measured values are reported in percentages based on the starting value.

The following materials are used as ABA polymers.

Sample 5: L-lactide-co-D, L-lactide-polyethyleneglycol-L-lactide-co-D, L-lactide having a weight ratio of 5% polyethylene glycol (PEG) and a molar weight of 2,000 daltons. Thus, the length of the A block is calculated as 19,000 Daltons in each case.

The following materials are used as AB polymers.

Sample 6: L-lactide-co-D, L-lactide-polyethyleneglycol having 5% by weight polyethylene glycol (PEG) and molar weight 5,000 Daltons. Therefore, the length of the A block is calculated as 95,000 Daltons.

result:

In ABA triblock copolymers, hydrolytic degradation after 18 weeks produces an intrinsic viscosity that constitutes only about 30% of the starting value. In AB diblock copolymer (Sample 6), a viscosity value of 9% of the starting value is obtained after 18 weeks.

1.3 Poly L-lactide-co-glycolide-polyethyleneglycol diblock or triblock copolymer

The following materials are used.

ABA type polymer having L-lactide-co-glycolide as a component of the A block and 5% polyethylene glycol 2000 (PEG 2000) as the B block and

AB type polymer with L-lactide-co-glycolide as a component of the A block and 5% polyethyleneglycol-MME 5000 (PEG-MME 5000) as the B block. The numbers 2000 and 5000 represent the molar weight of the PEG or PEG-MME in Daltons, respectively.

The value measured for intrinsic viscosity at time O is normalized to 100%. This corresponds to the value before the specimen was submerged in the hydrolysis bath. To measure degradation, the measured values are reported in percentages based on the starting value.

The following materials are used as ABA polymers.

Sample 7: L-lactide-co-glycolide-polyethyleneglycol-L-lactide-co-glycolide with 5% by weight polyethylene glycol (PEG) and molar weight 2,000 Daltons. Thus, the length of the A block is calculated as 19,000 Daltons in each case.

The following materials are used as AB polymers.

Sample 8: L-lactide-co-glycolide-polyethyleneglycol having 5% by weight polyethylene glycol (PEG) and molar weight 5,000 Daltons. Therefore, the length of the A block is calculated as 95,000 Daltons.

result:

Table 2 below provides an overview of the degradation rates of the polymers used.

i.v .: Intrinsic viscosity (measured by Uberode viscometer in chloroform at 25 ° C in 0.1% solution)

In both ABA triblock copolymers and AB diblock copolymers, hydrolytic degradation produces an intrinsic viscosity that constitutes only about 10% of the starting value after 18 weeks.

2. Mechanical test

To measure tensile strength, the specimens described below are prepared and measured according to ASTM D 638.

Sample 1: L-lactide-polyethyleneglycol with 1% polyethylene glycol (PEG) by weight and molar weight 2,000 Daltons. Thus, the length of the A block is calculated as 198,000 Daltons.

Sample 2: L-lactide-polyethyleneglycol having 5% by weight polyethylene glycol (PEG) and molar weight 2,000 Daltons. Therefore, the length of the A block is calculated as 38,000 Daltons.

Sample 3: L-lactide-polyethyleneglycol-L-lactide having 1% by weight polyethylene glycol (PEG) and molar weight of 6,000 Daltons. Thus, the length of the A block is calculated as 297,000 daltons in each case.

Sample 4: L-lactide-polyethyleneglycol-L-lactide having a weight ratio of 5% polyethyleneglycol (PEG) and a molar weight of 6,000 Daltons. Thus, the length of the A block is calculated as 57,000 daltons in each case.

Sample 5: L-lactide-polyethyleneglycol-L-lactide having 5% by weight polyethylene glycol (PEG) and a molar weight of 6,000 Daltons.

Sample 6: Polyethyleneglycol (PEG) at 5% by weight and molar weight 2,000 Daltons and L-lactide to D, L-lactide ratio 70:30 L-lactide-co-D, L-lactide-polyethyleneglycol -L-lactide-co-D, L-lactide.

Sample 7: Polyethyleneglycol (PEG) at 5% by weight and molar weight 5,000 Daltons and L-lactide to D, L-lactide ratio 70:30 L-lactide-co-D, L-lactide-polyethyleneglycol .

Sample 8: L-lactide-co-glycolide-polyethyleneglycol-L-lactide-co- with a weight ratio of 5% polyethylene glycol (PEG) and a molar weight of 2,000 daltons and an L-lactide to glycolide ratio of 85:15 Glycolide.

Sample 9: Polyethyleneglycol (PEG) at 5% by weight and molar weight 5,000 Daltons and L-lactide-co-glycolide-polyethyleneglycol with L-lactide to glycolide ratio 85:15.

Sample 10: Poly (L-lactide-co-glycolide) with an L-lactide to glycolide molar ratio of 85 ^: 15 ^* .

Sample 11: poly (L-lactide-co-DL-lactide) with a L-lactide to DL-lactide molar ratio of 70 ^: 30 ^* .

*: The tensile strength of these reference materials is measured according to DIN 53455 and the corresponding specimens are made according to DIN 53452.

Table 3 below provides an overview of the values obtained for the tensile strength of the specimens used.

i.v .: Intrinsic viscosity (measured by Uberode viscometer in chloroform at 25 ° C in 0.1% solution)

3. Polymer

3.1 Polylactide-Polyethylene Glycol-Polylactide Triblock Copolymer

35 g of PEG 6000 (6,000 Daltons in molecular weight, polyethyleneglycol with two terminal OH groups) are dried at 85 ° C. and 50 mbar / 2 hours. Add 3.5 kg of L-lactide. At 112 ° C., 965 mg of tin (II) -2-ethylhexanoate is added to the molten adduct. The mixture is bulk polymerized at 120 ° C. for 3 days. The crude polymer obtained is milled and extracted under the conditions described below. The polymer has an intrinsic viscosity of 2.63 dl / g and a residual monomer content of lactide of less than 0.5%. The content of PEG in the copolymer is 0.9% ( ¹ H-NMR). This corresponds to the molar weight for the A block of 338,000 g / mol per A block, based on PEG 6000. Glass transition temperature (T _g ) (measured by DSC, DSC 200 PC manufactured by Messer Netsch, heating rate: 10 ° K / min) is 60.8 ° C.

3.2 Poly -D, L- Lactide -No-L- Lactide - Polyethylene glycol - Poly -D, L- Lactide -No-L-lock tie De- Three blocks  Copolymer

175 g of PEG 2000 (molecular weight 2,000 Daltons, polyethyleneglycol with two terminal OH groups) are dried at 85 ° C. and 50 mbar / 2 hours. 2,520 g L-lactide and 980 g D, L-lactide are added. At 112 ° C., 1,003 mg of tin (II) -2-ethylhexanoate is added to the molten adduct. The mixture is bulk polymerized at 120 ° C. for 3 days. The crude polymer obtained is milled and extracted under the conditions described above. The polymer has an intrinsic viscosity of 0.86 dl / g and a residual monomer content of less than 0.5% lactide. The content of PEG in the copolymer is 4.8% ( ¹ H-NMR).

3.3 Poly -L- Lactide Co-glycolide Polyethylene glycol Eblock  Copolymer

125 g of PEG-MME 2000 (polyethylene glycol with molecular weight 2,000 daltons, terminal OH group and terminal methoxy group) are dried at 85 ° C. and 50 mbar / 2 hours. 2135.2 g L-lactide and 364.8 g glycolide are added. At 112 ° C., 717 mg of tin (II) -2-ethylhexanoate are added to the molten adduct. The mixture is bulk polymerized at 150 ° C. for 3 days. The crude polymer obtained is milled and extracted. The polymer has an inherent viscosity of 1.7 dl / g and residual monomer content of less than 0.5%. The content of PEG in the copolymer is 5.3% ( ¹ H-NMR).

3.4 Poly -D, L- Lactide -nose- Glycolide - Polyethylene glycol Eblock  Copolymer

236.7 g of PEG-MME 5000 (polyethylene glycol with molecular weight 5,000 daltons, terminal OH group and terminal methoxy group) are dried at 85 ° C. and 50 mbar / 2 hours. 2,537 g D, L-lactide and 1936 g glycolide are added. At 112 ° C., 1293 mg of tin (II) -2-ethylhexanoate is added to the molten adduct. The mixture is bulk polymerized at 150 ° C. for 3 days. The crude polymer obtained is dissolved in acetone and purified by sedimentation in water and then dried. The polymer has an intrinsic viscosity of 1.1 dl / g and residual monomer content of less than 0.5%. The content of PEG in the copolymer is 4.6% ( ¹ H-NMR).

3.5 Poly -L- Lactide - Polyethylene glycol - MME Eblock  Copolymer

35 g of PEG-MME 2,000 (polyethylene glycol with molecular weight 2,000 daltons, terminal OH group and terminal methoxy group) are dried at 85 ° C. and 50 mbar / 2 hours. Add 3,500 g of L-lactide. At 112 ° C., 965 mg of tin (II) -2-ethylhexanoate is added to the molten adduct. The mixture is bulk polymerized at 120 ° C. for 5-7 days. The crude polymer obtained is milled and extracted. The polymer has an inherent viscosity of 1.91 dl / g and residual monomer content of less than 0.5%. The content of PEG in the copolymer is 0.94% ( ¹ H-NMR).

3.6 Poly -L- Lactide -Nose-D, L- Lactide - Polyethylene glycol - MME Eblock  Copolymer

175 g of PEG-MME 5000 (polyethylene glycol with molecular weight 5,000 daltons, terminal OH group and terminal methoxy group) are dried at 85 ° C. and 50 mbar / 2 hours. 2,520.0 g L-lactide and 980 g D, L-lactide are added. At 112 ° C., 1,003 mg of tin (II) 2-ethylhexanoate is added to the molten adduct. The mixture is polymerized at 120 ° C. for 3 days. The crude polymer obtained is milled and extracted. The polymer has an inherent viscosity of 1.55 dl / g and residual monomer content of less than 0.5%. The content of PEG in the copolymer is 4.84% ( ¹ H-NMR).

3.7 Poly-L-lactide-co-glycolide-polyethyleneglycol-poly-L-lactide-co-glycolide triblock copolymer

65 g of PEG-6000 (molecular weight 6,000 Daltons, polyethylene glycol with two terminal OH groups) are dried at 85 ° C. and 50 mbar / 2 hours. 5,496.1 g L-lactide and 938.9 g glycolide are added. At 112 ° C., 1775 mg of tin (II) 2-ethylhexanoate is added to the molten adduct. The mixture is bulk polymerized at 150 ° C. for 3 days. The crude polymer obtained is milled and extracted. The polymer has an intrinsic viscosity of 2.7 dl / g and a residual monomer content of less than 0.5%. The content of PEG in the copolymer is 1.0% ( ¹ H-NMR).

3.8 Poly -D, L- Lactide -nose- Glycolide - Polyethylene glycol - Poly - D, L - Lactide Co-glycolide Three blocks  Copolymer

499.5 g of PEG 6000 (molecular weight 6,000 Daltons, polyethylene glycol with two terminal OH groups) are dried at 85 ° C. and 50 mbar / 2 hours. 2,537.0 g of D, L-lactide and 1,963.0 g of glycolide are added. At 112 ° C., 1365 mg of tin (II) -2-ethylhexanoate is added to the molten adduct. The mixture is bulk polymerized at 150 ° C. for 3 days. The crude polymer obtained is dissolved in acetone and purified by sedimentation in water and then dried. The polymer has an inherent viscosity of 0.75 dl / g and residual monomer content of less than 0.5%. The content of PEG in the copolymer is 10.05% ( ¹ H-NMR).

4. Tablet

The milled products of Examples 3.1 to 3.3 and 3.5 to 3.7 are placed in a 16 L extraction cartridge. After closing the cartridge, the contents are extracted with pressure-liquefied carbon dioxide.

Extraction condition:

Time / pressure: 1 hour at 90 bar, 4 hours at 300 bar

Temperature: below 10 ℃

Flow of CO2: about 120kg / h

This purification example can be performed similarly for other polymers.

Claims (61)

AB or ABA type block copolymers, A is a polyester block, B is a polyether block, Form AB is represented by Formula I, ABA type is represented by Formula II, B blocks constitute a ratio of 0.1 to 4% by weight, A block a) D-lactide and L-lactide, b) L-lactide and glycolide, c) D, L-lactide and glycolide, d) L-lactide and ε-caprolactone, e) L-lactide and dioxanone, f) L-lactide and trimethylene carbonate, g) L-lactide, D-lactide, meso-lactide or DL-lactide, h) L-lactide, i) DL-lactide, j) statistically distributed monomer units of L-lactide, D-lactide, meso-lactide or DL-lactide and ε-caprolactone, k) statistically distributed monomer units of L-lactide, D-lactide, meso-lactide or DL-lactide and dioxanone, and l) synthesized from monomer components or mixtures thereof selected from the group consisting of L-lactide, D-lactide, meso-lactide or DL-lactide and statistically distributed monomeric units of trimethylene carbonate, AB or ABA type block copolymers. Formula I E- (OD-CO-) _n- (O-CH ₂ -CH _2- ) _m -OF In the above formula (I) Structural unit E-(-OD-CO-) _n -forms block A, -(O-CH ₂ -CH _2- ) _m -forms block B, D is, independently of each other, for each n unit:-(CH (CH ₃ )-) _x ,-(CH _2- ) _x ,-(CH ₂ -O-CH ₂ -CH _2- ) or-(CH ₂ -CH ₂ -CH ₂ -O-), x is 1, 2, 3, 4 or 5, E and F are independently of each other H, methyl or ethyl, n and m are statistical averages and are integers greater than 1 independently of each other. (II) E (-OD-CO) _n- (O-CH ₂ -CH _2- ) _m -O- (CO-DO-) _{n '} -E In the above formula (II) Structural units E (-OD-CO) _n -and E-(-OD-CO-) _{n '} -form block A, -(O-CH ₂ -CH _2- ) _m -forms block B, D is, independently of each other, for each n or n 'unit:-(CH (CH ₃ )-) _x ,-(CH _2- ) _x ,-(CH ₂ -O-CH ₂ -CH _2- ) or -(CH ₂ -CH ₂ -CH ₂ -O-), x is 1, 2, 3, 4 or 5, E is H, methyl or ethyl, n, n 'and m are statistical averages and are integers greater than 1 independently of each other. The AB or ABA type block copolymer according to claim 1, wherein the weight ratio of the B block is 1 to 3% by weight. A type AB or ABA type block copolymer, represented by Formula I or Formula II according to claim 1, characterized in that the A blocks are synthesized from statistically distributed units of L-lactide and DL-lactide. The AB or ABA type block copolymer according to claim 3, wherein the molar ratio of L-lactide in the A block is 60 to 90%. Represented by formula (I) or (II) according to claim 1, wherein the A block consists of statistically distributed units of L-lactide and glycolide, wherein the molar ratio of L-lactide is 85 to 99% , AB or ABA type block copolymer. The AB or ABA type block copolymer according to claim 5, wherein the molar ratio of L-lactide in the A block is 87 to 95%. Represented by Formula I or Formula II according to claim 1, characterized in that the A block consists of statistically distributed units of DL-lactide and glycolide and has an intrinsic viscosity of greater than 0.8 dl / g, AB or ABA type block copolymers. The AB or ABA type block copolymer according to claim 7, wherein the molar ratio of DL-lactide in the A block is 50 to 80%. The AB or ABA type block copolymer according to claim 1, wherein the A block is composed of L-lactide or DL-lactide and a statistically distributed unit of dioxanone. The AB or ABA type block copolymer according to claim 1, wherein the A block is composed of statistically distributed units of L-lactide or DL-lactide and trimethylene carbonate. The AB or ABA type block copolymer according to any one of claims 1 to 10, wherein the number average block length of the B blocks is 500 to 10,000 Daltons. The AB-type or ABA-type block copolymer according to claim 11, wherein the number average block length of the B blocks is 600 to 8,000 Daltons. 13. The AB or ABA type block copolymer according to claim 12, wherein the number average block length of the B blocks is 1,000 to 8,000 Daltons. The AB type or ABA type block copolymer according to any one of claims 1 to 10, wherein the intrinsic viscosity is 0.1 to 6 dl / g. The AB type or ABA type block copolymer according to claim 14, wherein the intrinsic viscosity is 0.5 to 5 dl / g. 16. The type AB or ABA type block copolymer according to claim 15, wherein the intrinsic viscosity is 0.6 to 3 dl / g. The type AB or ABA type block copolymer according to claim 16, wherein the intrinsic viscosity is 0.7 to 2.75 dl / g. Mixing and melting poly (ethyleneglycol) with one or two free terminal OH groups with at least one monomer and / or dimer of formula III, (a), Adding the metal catalyst to the homogeneous mixture obtained in step (a) (b), (C) polymerizing the mixture of step (b) at a reaction temperature above the melting point of the reactants used for a reaction time of 24 hours to 5 days, (D) purifying the crude polymer obtained in step (c) by precipitation or extraction from a solvent, and A process for producing an AB or ABA type block copolymer according to any one of claims 1 to 10, comprising the step (e) of grinding the polymer obtained in step (d). (III)

In formula (III) above, D in each unit of -OD-CO is independently of each other-(CH (CH ₃ )-) _x ,-(CH _2- ) _x ,-(CH ₂ -O-CH ₂ -CH _2- ) or-(CH ₂ -CH ₂ -CH ₂ -O-), x is 1, 2, 3, 4 or 5, z is an integer of 1 or more. 19. The method according to claim 18, wherein the poly (ethylene glycol) used in step (a) is previously dried. The preparation of type AB or ABA type block copolymers according to claim 18, characterized in that tin (II) or tin (II) ethylhexanoate at a concentration of 30 to 200 ppm is used as the metal catalyst in step (b). Way. The preparation of AB or ABA type block copolymers according to claim 18, wherein tin (II) or tin (II) ethylhexanoate at a concentration of 50 to 100 ppm is used as the metal catalyst in step (b). Way. 19. The method of claim 18, wherein the polymerization in step (c) is carried out at a temperature in the range of 100 to 160 ° C. 19. The method of claim 18, wherein the polymerization in step (c) is carried out at a temperature in the range of 100 to 140 ° C. 19. The method of claim 18, wherein the polymerization in step (c) is carried out at a temperature in the range of 110 to 130 ° C. 19. The process according to claim 18, wherein the polymerization in step (c) is carried out over a reaction time of 2 to 5 days. 19. Form AB or according to claim 18, characterized in that the purification in step (d) is carried out by extraction and the crude polymer obtained in step (c) is extracted with a solvent or carbon dioxide selected from n-alkane or cycloalkane. Method for producing an ABA type block copolymer. 19. A process according to claim 18, wherein the purification in step (d) is carried out by extraction and the crude polymer obtained in step (c) is extracted with carbon dioxide. An implant comprising an AB or ABA type block copolymer according to any one of claims 1 to 10. The implant of claim 28, wherein the implant is made entirely from one material. The implant of claim 28, as a suture material anchor, to fix a hard tissue fracture, to a spinal implant, to close and fix a blood vessel or other vessel, as a stent, or to fill a cavity or hole in a tissue defect. The implant as stent according to claim 28 comprising an active substance selected from cell growth inhibitors. The implant of claim 28, in the form of a screw, pin, plate, nut, anchor, down, film, membrane or mesh. Drying (a) a type AB or ABA type block copolymer of formula I or formula II according to any one of claims 1 to 10; Converting the AB or ABA type block copolymer into the molten state in an injection molding machine (b), Injecting the polymer melt into a mold of desired dimensions (c), (D) cooling the polymer melt in an injection mold and A method of making an implant comprising an AB or ABA type block copolymer according to any one of claims 1 to 10, comprising the step (e) of removing the molding from the injection mold. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete